MicroRNAs (miRNAs) are single-stranded endogenous non-coding small RNA molecules of about 18-25 nucleotides in length, which negatively regulate gene expression either by binding to the 3′ UTR leading to inhibition of translation or degradation of specific target mRNAs. A single miRNA can directly regulate multiple target genes, and thereby control expressions of multiple proteins involved in diverse signaling pathways (Bartel D P. MicroRNAs: target recognition and regulatory functions. Cell 2009; 136:215-233). The expressions of miRNAs differ according to organ development and tissue differentiation (Rosenfeld N, Aharonov R, Meiri E, et al. MicroRNAs accurately identify cancer tissue origin. Nat Biotechnol 2008; 26:462-469). MiRNAs are known to regulate diverse biological processes (Huang Y, Shen X J, Zou Q, Wang S P, Tang S M Zhang G Z. Biological functions of microRNAs: a review. Journal of physiology and biochemistry 2011; 67:129-139), and are associated with apoptosis and cancer by regulating the translation of oncogenes and tumor suppressors (Lee Y S Dutta A. MicroRNAs in cancer. Annu Rev Pathol 2009; 4:199-227). Recent studies have demonstrated dysregulation of miRNAs in the initiation and progression of various cancers (Lovat F, Valeri N Croce C M. MicroRNAs in the pathogenesis of cancer. Seminars in oncology 2011; 38:724-733).
Glioblastoma multiforme (GBM, World Health Organization [WHO] grade IV glioma) is the most common and aggressive type of primary adult brain cancer. The standard treatment for newly diagnosed GBM is surgical resection followed by a combination of radiation and chemotherapy (Stupp R, Mason W P, van den Bent M J, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352:987-996). Despite advances in therapeutic approaches and the understanding of the molecular mechanisms and genetics of GBM (Bai R Y, Staedtke V Riggins G J. Molecular targeting of glioblastoma: Drug discovery and therapies. Trends in molecular medicine 2011; 17:301-312, Kesari S. Understanding glioblastoma tumor biology: the potential to improve current diagnosis and treatments. Seminars in oncology 2011; 38 Suppl 4:S2-10), the overall survival rate is very poor and the median lifespan of GBM patients is limited to 10 to 15 months. This lifespan has only minimally improved over a period of decade even with therapeutic interventions. The major problem is that most GBM (about 90% of cases) recurs within or adjacent to the original tumor bed (Joki T, Carroll R S, Dunn I F, Zhang J, Abe T Black P M. Assessment of alterations in gene expression in recurrent malignant glioma after radiotherapy using complementary deoxyribonucleic acid microarrays. Neurosurgery 2001; 48:195-201; discussion 201-192). Currently, there is no standard treatment for recurrent GBM, although additional surgery, chemotherapy, and radiotherapy are used. Therefore, it is urgently necessary to determine novel molecular targets, concepts, and approaches to treat this devastating disease.
Since human brain tumor stem cells have been identified, researches on the resistance of GBM to chemoradiotherapy have been conducted. The resistance is attributed to a DNA repair proficiency, a multitude of dysregulated growth factor signaling pathways, and to the particular biologic behaviors of cancer stem-like cells (Haar C P, Hebbar P, Wallace G Ct, et al. Drug Resistance in Glioblastoma: A Mini Review. Neurochemical research 2012). Although the molecular and genetic changes in recurrent GBM have been studied, the causes and pathogenesis of resistance in recurrent GBM have not yet been clearly identified.
As postoperative radiotherapy does not provide great benefits to GBM patients, several attempts have been made to find suitable adjuvant chemotherapies to prevent the recurrence of GBM. A novel approach for the molecular characterization of tumors is based on the expression profiling of miRNAs. Over the past few years, several miRNAs involved in GBM pathogenesis have been identified (Novakova J, Slaby O, Vyzula R Michalek J. MicroRNA involvement in glioblastoma pathogenesis. Biochem Biophys Res Commun 2009; 386:1-5, Srinivasan S, Patric I R Somasundaram K. A ten-microRNA expression signature predicts survival in glioblastoma. PLoS One 2011; 6:e17438); however, the physiological roles of only small fraction of the identified miRNA are understood. Moreover, global miRNA signature involved in the resistance of recurrent GBM has never been investigated.